Postdoc Seminar Series – Tim Calamaras & how we can protect our hearts

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Today Tim Calamaras a great postdoc from Tufts Medical Center spoke about “Identifying PKG1a interacting proteins to discover novel cardioprotective molecules”

  • 1 out of 5 people over 40 will suffer from heart failure
  • there are multiple causes
    • Coronary artery disease
    • Mycocardial infarction (hear attack)
    • Obesity/Diabetes (metabolic changes)
    • High blood pressure

High Blood Pressure

  • Results in compensatory cardiac remodeling
  • left ventricle (LV) hypertrophy
  • Leads to “adverse” cardiac remodeling
  • decreased cardiac contractile function

PKGIa

  • Set/Thr kinase present in cardiomyocytes and vascular smooth muscle cells
  • Vasodilation in vascular smooth muscle cell substrates
  • In cardiocmyocyte prevents cardiac remodeling
  • Has a leucine zipper, mutation of this N terminal domain, kinase function is intact, but can’t bind other proteins (PKG-LZM)
  • Proteins can interact via LZ domain

Surgical model of high blood pressure: thoracic aortic construction (TAC)

  • study PKG-LZM mice
  • more death follow TAC
  • less ability to contract LV
  • more LV hypertrophy
  • LZM hearts have impaired MKK4-JNK activation

Candidate search: LZ containing protein regulator of JNK signaling

  • Potential PKGIa substrate: MLK3
  • MLK3 is LZ containing and regulates JNK pathway

PKGIalpha and MLK3 physically interact and promote JNK signaling

  • Co-IP shows physical interaction
  • PKGIalpha phosphorylates and activates MLK3 kinases activity

MLK3-/- mice have increased LV hypertrophy after TAC (we haven’t figured out the signalng yet 🙂

 

 

 

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